Tumor specific targeting, is an intensive research field within oncology. The rationale is to reduce side effects and increase the drug dose that can be delivered to the cancer patient thus enhancing the therapeutic efficacy.
Examples of such targeting are antibody oriented targeting, i.e. immuno-targeting, and controlled drug delivery systems using various polymers as drug carriers (1, 2, 3, 4, 5, 6).
Tabata et al (11) describes intravenous administration of dextran with negative charges. This gives very low specific accumulation of the dextran to the tumor. The specific accumulation or the target to non-target ratio (ttn-ratio) is never exceeding 10 (shown in FIGS. 8 and 9, page 219).
Syrigos et al (12) describes intravesical administration of radiolabelled tumor-associated monoclonal antibody giving a specific accumulation or target to non-target ratio (ttn-ratio) ranging between 2 and 6.
This invention relates to compounds that, when administered locally, intratumorally or intracavitarily, show unexpectedly high accumulation to tumors and that can deliver various functional groups, including both therapeutic or imaging agents to these sites, to mediate tumor therapy or imaging.
The inventor has discovered that due to the ionic properties of tumors, polymers with an appropriate charge can be selectively targeted to tumors through electrostatic interactions in an ion exchange like reaction. The charged character of tumors could be explained by tumors having enlarged blood vessel surface, abnormal interstitium, and high content of sialic-acid at the cell surface. All these contain charged, mainly anionic, carbohydrates (sulphated carbohydrates) and proteins (collagen) (7, 8). The selective accumulation is unexpectedly high when administered locally, intratumorally or intracavitarily.
By using these charged groups characteristic for tumors as target, the invention avoids the general limitations of tumor specific targeting, such as low affinities between targeting compound and tumor etc. Targeting tumors with compounds according to the invention avoids the problem of tumor heterogeneity, i.e. the limitation of antibody-based cancer therapies that target only a single type of tumor cells in a tumor containing multiple cell types. Further more, tumor therapy or imaging using compounds according to present invention do not require an initial pre-targeting step, as many prior art methods do.
The compounds according to the invention show, when administered locally, intratumorally or intracavitarily, unexpectedly high affinities for tumors, i.e. they have an unexpectedly high target to non-target (ttn) ratio (see Example 2). The charge of the compounds can be adapted to the charge of the tumor to be treated, thereby increasing the target to non-target ratio of the compound to the tumor. When looking at the general properties of solid tumors, it seems probable that the principle of the invention, i.e. selective accumulation in tumor tissue through interactions between the charges of the tumor and the polymer, is functional in most human solid tumors.
In preferred embodiments, the compounds of the invention comprise a targeting compound, which is a charged polymer that binds selectively to the tumor through electrostatic interactions. The targeting compound is modified to include a functional group, which may be part of the polymer or attached to the polymer as a tag. Where the compound is to be used therapeutically the functional group is a toxin, a drug, a radioactive molecule or a precursor thereof. Where the compound is to be used for tumor imaging rather than therapy, the functional group may also be a detectable label, such as a radioactive molecule.
The compounds according to the invention are for local, i.e. intracavitary or intratumoral administration. Examples of tumors suitable for such administration are tumors growing in body-cavities such as urinary bladder tumors, ovarian tumors, certain brain tumors, and for intratumoral administration, pancreatic tumors, and head and neck tumors. When the compounds according to the invention are administered locally, intratumorally or intracavitarily the specific accumulation or ttn-ratio ranges between 700 and 2050, which far exceeds specific accumulation when administered according to prior art.
The compounds according to the invention comprise a charged polymer, which causes the targeting, and a functional group, which causes the therapy or imaging.
In preferred embodiments the targeting polymer of the compound according to the invention is a poly-alcohol, such as dextran. When using dextran, a preferred molecular weight is between 103-106 Dalton. In a preferred embodiment the charged side groups of the polymer are amino acids having charged side chains, or derivatives thereof, such as ornithine, lysine, arginine, histidine, glutamic acid, aspartic acid etc. The amino acids are coupled to dextran by activating the hydroxyl groups of dextran through partial oxidation to aldehydes which react with the free amino groups of the amino acids. This procedure is described in Foster, R L. 1975 (10). An example of a resulting compound (lysine-dextran) according to the invention is shown in FIG. 1. In a preferred embodiment an amino acid is coupled to between 15-30% of the glucose residues of dextran.
The resulting charge of the compound can be positive, negative or neutral depending of the requirements, i.e. the electrostatic properties of the type of tumor to be targeted.
Examples of the functional group of the compound according to the invention include drugs (e.g. antibiotics, anti-virals, anti-fungals), toxins (e.g. ricin), radio-nuclides (e.g. Cu-64, Cu-67, Sr-89, Y-90, Tc-99m, I-131, Sm-153, Ho-166, Re-186, Re-188, Bi-212), hormone antagonists (e.g. tamoxifen), heavy metal complexes (e.g. cisplatin), oligo-nucleotides (e.g. antisense oligo-nucleotides), chemotherapeutic nucleotides, peptides, non-specific (non-antibody) proteins, boron containing compounds (e.g. carborane), photodynamic agents (e.g. rhodamine), enediynes (e.g. calichesmicins), and transcriptions based pharmaceuticals.
Coupling of the functional group could be done either directly to the polymer or through a bifunctional chelate, such as an aminated radio-metal chelate. Direct coupling of the functional group to the poly-alcohol could be achieved in the same manner as the charged side-groups are coupled to the poly-alcohol. The binding of the functional group must not allow release of the functional group in vivo.
The compounds according to the invention can be administered alone, or in conjunction with a pharmaceutically acceptable carrier.
This invention will now be described in greater detail by reference to the following non-limiting examples in which: